Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11](Br)=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3]1.[CH3:34][S-:35].[Na+].C(O)(=O)C>CN(C=O)C>[O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([S:35][CH3:34])=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3]1
Reactant: C[S-]
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 14; 500 mg, 0.93 mmol) was dissolved in DMF (10 ml). Sodium methanethiolate (200 mg, 2.85 mmol) was added and the mixture was stirred for 2 hours at 50° C. Acetic acid (0.4 ml) was added and the solvent was evaporated under reduced pressure. The residue was extracted with EtOAc/water. The EtOAc layer was separated, dried and evaporated under reduced pressure to give, the title compound 450 mg (96%). NMR. (300 MHz) 0.7–0.8 (m, 6H), 1.0–1.6 (m, 12H), 2.2 (s, 2H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.8 (s, 2H), 6.6 (s, 1H), 6.9–7.1 (m, 3H), 7.2–7.4 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([C:12]([F:15])([F:14])[F:13])[N:7]=[CH:6][N:5]=1)[CH3:2].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[CH2:1]([O:3][C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]([F:14])([F:15])[F:13])[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncnc(C(F)(F)F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1ncnc(C(F)(F)F)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A solution of 3.82 g (17.2 mmoles) of 4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 50 ml of methanol was added, with ice-cooling, into a solution of 1.7 g (45.7 mmoles) of sodium borohydride dissolved in 50 ml of methanol. The mixture was stirred at 0° C. for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 3.77 g (yield: 97.8%) of (4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=2[CH3:18])C=CC=CC=1.O=C1C2C(=CC=CC=2)C(=O)[N:33]1[CH2:42][CH2:43][CH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH:48]=O>>[CH3:18][C:11]1[CH2:12][CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[C:10]=1/[CH:9]=[CH:48]/[C:47]1[CH:46]=[C:45]([CH2:44][CH2:43][CH2:42][NH2:33])[CH:52]=[CH:51][CH:50]=1
Reactant: CC1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: CC1=C(/C=C/c2cccc(CCCN)c2)C(C)(C)CCC1

Procedure:
(E)-3-(3-(2-(2,6,6-Trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine was prepared by coupling triphenyl((2,6,6-trimethylcyclohex-1-enyl)methyl)phosphonium bromide (24) (Scheme 8) with 3-(3-(1,3-dioxoisoindolin-2-yl)propyl)benzaldehyde (29) (Scheme 9).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([OH:12])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1.CS(O[C@H:18]([C@@H:20]1[CH2:24][C:23](=[O:25])[N:22]([C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH3:27])[CH2:21]1)[CH3:19])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:12][C@@H:18]([C@H:20]2[CH2:21][N:22]([C@@H:26]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:25])[CH2:24]2)[CH3:19])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1
Reactant: Cc1cnn2cc(Cl)nc(O)c12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C)c34)CC2=O)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 32.9 %

Procedure:
A mixture of 6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-ol 5.52 (48 mg, 0.262 mmol), (S)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethyl methanesulfonate 1.30 (135 mg, 0.394 mmol), and cesium carbonate (136 mg, 0.417 mmol) in DMF (2 mL) was heated at 90° C. After 5 hours, reaction mixture was cooled to rt, poured into water, and extracted with ethyl acetate. Combined organics were washed with 50% brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate/hexanes) to yield (R)-4-((R)-1-((6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 5.53 (37 mg).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[NH:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:12].Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2[CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1.O>CC(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C@@H:10]([NH:9][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][N:34]3[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH3:28])=[C:15]([NH:21][C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[CH:16]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ncccn1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1Nc1ncccn1
Temperature: 80 °C

Procedure:
Triethylamine (518 μl, 3.72 mol) was added to (S)-2-amino-N-[4-fluoro-2-(pyrimidin-2-ylamino)phenyl]propionamide hydrochloride salt 161b (289 mg, 0.93 mmol) and 6-chloro-9-(tetrahydropyran-2-yl)purine (265 mg, 1.10 mol) in IPA (5.0 ml) and heated to 80° C. overnight. The reaction was poured into water and the aqueous layer extracted into EtOAc (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% 2M ammonia methanol/DCM) to yield the title compound as a 1:1 mixture of diastereomers (236 mg, 0.50 mmol, 53%). LCMS RT 2.63 min [M+H]+ 478.2.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CSc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
To a stirred solution of 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (1.02 g, 2.61 mmol) from Step 3 of this Example in DCM (50 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (707 mg, 2.87 mmol) and the mixture was allowed to warm to rt and stirred for a further 45 min. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to afford 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.06 g, 100%) as a cream solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.18 (s, 1H), 8.08-8.12 (m, 2H), 7.61 (m, 1H), 7.50 (d, J=9 Hz, 1H), 5.68 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 407 and 409 (M+H)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[S:11]([N:21]([CH2:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH2:28][OH:29])=[O:25])[CH3:22])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[S:11]([N:21]([CH2:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][C@H:27]1[CH:28]=[O:29])=[O:25])[CH3:22])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N2CCC[C@H]2CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N2CCC[C@H]2C=O)cc1
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
In the next step, a solution of dimethyl sulfoxide (DMSO) (35.3 ml, 0.491 mol) in methylene chloride (970 ml) is added dropwise, over a period of 2.5 hours at -60° C. under an atmosphere of nitrogen, to a solution of oxalyl chloride (44.7 ml, 0.491 mol) in methylene chloride (970 ml), and the mixture is stirred for a further five minutes. A solution of N-tosylsarcosyl-L-prolinol (80 g, 0.245 mol) in methylene chloride (950 ml) is then added dropwise to the mixture over a period of 75 minutes, and the mixture is stirred for a further thirty minutes. Triethylamine (348 ml, 2.45 mol) is then added dropwise thereto over a period of ten minutes, and the mixture is stirred for a further ten minutes. After brought back to room temperature, the mixture is washed with water (2 l×2) and the organic layer is concentrated to dryness under reduced pressure. The residue is dissolved in ethanol (320 ml), and the solution is vigorously stirred for 15 minutes after addition of a saturated aqueous solution of sodium hydrogen carbonate (250 ml) and water (438 ml). The ethanol is then distilled off under reduced pressure, and water (600 ml) is added to the residue. The mixture is extracted with chloroform (300 ml) and ether (500 ml×2) and the organic layers are discarded. The aqueous layers are adjusted with potassium carbonate to a pH higher than 10 and extracted with chloroform. The organic layer is separated, washed successively with water (500 ml×2), 1N hydrochloric acid (500 ml) and water (500 ml), dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give N-tosylsarcosyl-L-prolinal (49.5 g, 62.3%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20]>O1CCOCC1.C(O)C>[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20].[CH2:13]([NH:17][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4])[CH2:14][CH2:15][CH3:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCN
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCNCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C

Procedure:
18 g of D-glucose are suspended in 200 ml of dioxane and 100 ml of ethanol, and 7.3 g of butylamine are added. The mixture is warmed to 70° C. and, after 10 minutes, 9.0 g anhydrous oxalic acid is added. The temperature is maintained for 4 hours. After cooling to room temperature, the product crystallizes out. The solid is filtered off with suction, rinsed five times with 50 ml of ethanol each time and dried in vacuo.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:42]1[C:54]2[NH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[C:45]([O:55][CH2:56][CH:57]([OH:65])[CH2:58][N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:44][CH:43]=1>CN(C=O)C.C(Cl)Cl>[CH:42]1[C:54]2[NH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[C:45]([O:55][CH2:56][CH:57]([OH:65])[CH2:58][N:59]2[CH2:64][CH2:63][N:62]([C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[CH2:61][CH2:60]2)=[CH:44][CH:43]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: OC(COc1cccc2[nH]c3ccccc3c12)CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])o1)N1CCN(CC(O)COc2cccc3[nH]c4ccccc4c23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
To a solution of 5-Nitrofuroic acid (1.56 g, 9.9 mmol) in DMF (30 mL) was added DIPEA (4.3 mL, 24.8 mmol), EDCI (3.18 g, 16.5 mmol), HOBt (0.44 g, 3.3 mmol) followed by the 1-(9H-carbazol-4-yloxy)-3-piperazin-1-ylpropan-2-ol (2.7 g, 8.3 mmol, prepared following the procedure described above in step 11, example 26). The reaction mixture was stirred at room temperature for 12 hours and was diluted with DCM (100 mL), washed with water and brine solution. The organic layer was dried on anhydrous Na2SO4, concentrated and purified by silica gel column chromatography, using hexane/EtOAc (4:6) to afford the title compound as yellow colored solid (2.0 g, 51% yield) with m.p: 178-181° C. 1H NMR (400 MHz, DMSO): δ 2.30-2.60 (m, 4H), 2.67-2.69 (m, 2H), 3.63-3.69 (m, 4H), 4.13-4.21 (m, 3H), 5.08 (s, 1H), 6.69 (d, 1H, J=8.0 Hz), 7.06 (d, 1H, J=8.0 Hz), 7.14 (t, 1H, J=8.0 Hz), 7.24-7.36 (m, 3H), 7.44 (d, 1H, J=8.0 Hz), 7.66 (d, 1H, J=4.0 Hz), 8.22 (d, 1H, 8.0 Hz), and 11.25 (s, 1H). MS m/z: 464.8 (M+1).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.S(=O)(=O)(O)O.[N+]([O-])(O)=O>[Ni].C(O)C>[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: CC(=O)c1ccccc1

Procedure:
With the nickel catalyst, if very pure m-nitroacetophenone is used (i.e., 100% by GLC as obtained, for example, by crystallization from ethanol) the hydrogenation will not occur or will occur slowly. Where crude (less than 100% purity) m-nitroacetophenone is used-the impurities present being acidic sulfuric acid, nitric acid, or other acid material contained in the m-nitroacetophenone as obtained directly from the nitration of acetophenone without further purification-the process is operable. Crude m-nitroacetophenone when suspended in water gives a strongly acid system with a pH of 2.6 to 3.2. If very pure m-nitroacetophenone is used and fails to hydrogenate, the addition of a few drops of sulfuric acid to the aqueous suspension will permit hydrogenation to occur to yield the desired product.
Reaction SMILES: C[C:2]1([N:23]=[N+]=[N-])[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:3]1[O:4][C:5](=[O:7])[CH3:6].[H][H].O1CCC[CH2:29]1>[Pd]>[CH3:29][NH:23][CH:2]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:3]1[O:4][C:5](=[O:7])[CH3:6]
Reactant: [H][H]
Reactant: C1CCOC1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)C(C)(N=[N+]=[N-])O[C@@H]1C(=O)O
Agent: [Pd]
Product: CNC1O[C@H](C(=O)O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: -15 °C

Procedure:
Next, 359 mg (1 mmol) of the methyl 2,3,4-tri-O-acetyl glucopyranuronosyl azide was added to 50 ml of tetrahyrofuran containing 50 mg of 10% Pd on carbon. The solution was cooled to -15° C. and was shaken under 40 psl of hydrogen for 1 hour, filtered and concentrated to dryness to produce methyl 2,3,4,-tri-O-acetylglucopyranuronosyl amine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[ClH:1].[OH:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:43][CH2:44]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: Cl

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. Purification: ISCO Combi-flash RF system eluting with 0 to 5% MeOH in EtOAc. The pure product was dissolved in 1 mL of 12M HCl then concentrated in vacuo to afford the title compound as the HCl Salt: 1H NMR (400 MHz, DMSO-d6) δ10.60 (s, 1H), 9.10 (br. s., 1H), 8.37 (s, 1H), 7.43 (br. s., 1H), 7.31 (d, J=8.59 Hz, 1H), 7.07 (s, 1H), 6.92 (d, J=7.83 Hz, 1H), 4.48 (s, 2H), 3.92-4.05 (m, 7H), 3.44-3.56 (m, 1H), 3.23-3.35 (m, 2H), 3.06 (s, 3H), 1.92 (d, J=10.36 Hz, 2H), 1.54-1.75 (m, 4H), 1.23-1.33 (m, 2H), 1.19 (t, J=7.07 Hz, 6H). MS (ES+): m/z: 678.24 [MH+]. HPLC: tR=3.37 min (Micromass ZQ3: polar—5 min).
Reaction SMILES: FC1C=CC(CC(Cl)=O)=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:22]=[C:23]=[O:24])=[O:21])=[CH:15][CH:14]=1.[F:25][C:26]1[CH:27]=[C:28]([NH2:39])[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(Cl)Cl.[Ag]OC#N>[F:25][C:26]1[CH:27]=[C:28]([NH:39][C:23]([NH:22][C:20](=[O:21])[CH2:19][C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)=[O:24])[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccncc2)c(F)c1
Agent: N#CO[Ag]
Agent: O=C(Cl)Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccncc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
Silver cyanate (0.912 g, 6.08 mmol, 1.05 eq) was added to a solution of 4-fluorophenylacetyl chloride (Aldrich, 0.794 mL, 5.79 mmol, 1.0 eq) in toluene (16 mL) at room temperature shielded from light. The reaction mixture was heated to reflux for 60 minutes and then cooled to room temperature. The reaction mixture was filtered (Acrodisc, PTFE 0.2 μM) and the resultant 2-(4-fluorophenyl)acetyl isocyanate solution (0.36 M, 0.75 mL, 0.27 mmol, 1.1 eq) was added to a solution of 3-fluoro-4-(pyridin-4-yloxy)benzenamine (0.050 g, 0.245 mmol, 1.0 eq) in CH2Cl2 (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h, quenched with saturated aqueous NaCl solution and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 0-5% MeOH in CHCl3) to afford the title compound (0.043 g, 46%) as a solid. 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.60 (s, 1H), 8.47 (s, 2H), 7.77-7.80 (m, 1H), 6.92-7.48 (m, 8H), 3.75 (s, 2H); MS (ESI+) m/z 384 (M+H)+; HRMS (ESI+) calcd.: 384.1160. found: 384.1147.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:4]=2[N:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[Si:24]([O:18][CH2:17][C:15]1[CH:14]=[CH:13][C:5]2[N:6]([CH:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)[C:2]([NH2:1])=[N:3][C:4]=2[CH:16]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Nc1nc2cc(CO)ccc2n1C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)nc(N)n2C1CCCCC1
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of (2-Amino-1-cyclohexyl-1H-benzoimidazol-5-yl)methanol (0.650 g, 0.00265 mol) and 1H-Imidazole (0.4149 g, 0.006094 mol) in N,N-Dimethylformamide (10 mL) was added tert-Butyldimethylsilyl chloride (0.4393 g, 0.002914 mol) and the mixture stirred for 1 hour. The mixture was diluted with ethyl acetate, washed with saturated socium bicarbonate, dried and concentrated. The residue was taken up in methylene chloride containing 0.1% triethylamine and purified by flash chromatography with a gradient of from 0 to 10 percent methanol. The product fractions were concentrated to give 539 mg of the product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:25]([O:27]CC)=[O:26])[C:7](=[O:24])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([NH2:22])=[CH:17][C:16]=2[Cl:23])[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:25]([OH:27])=[O:26])[C:7](=[O:24])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([NH2:22])=[CH:17][C:16]=2[Cl:23])[CH:10]=[CH:9]3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(C)c(N)cc3Cl)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccn3c(=O)c(C(=O)O)cc(C4CC4)c3c2C)c(Cl)cc1N
Temperature: 60 °C

Procedure:
A solution of ethyl 1-cyclopropyl-8-(4-amino-2-chloro-5-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (70 mg, 0.171 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (29 mg, 0.690 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 30 as yellow solid (51 mg, 78%). ESI-MS m/z: 383 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.28 (d, J=7.5 Hz, 1H), 8.24 (s, 1H), 7.43 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 6.81 (s, 1H), 5.55 (s, 2H), 2.75 (s, 3H), 2.54-2.52 (m, 1H), 2.07 (s, 3H), 1.03-1.01 (m, 2H), 0.74-0.70 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=1.O1CCCC1.CO.[OH-].[K+]>O>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)c(F)c(OCCOC)c3[nH]2)S1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
To a mixture of ethyl {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (0.30 g), tetrahydrofuran (12 mL) and methanol (12 mL) was added a solution of potassium hydroxide (85%, 0.18 g) in water (10 mL). The mixture was stirred at room temperature for 15 h and then partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (267 mg, 94%) as pale yellow crystals. MS 524 (MH+).